title: A novel small molecule HSP90 inhibitor, NXD30001, differentially induces heat shock proteins in nervous tissue in culture and in vivo.
abstract: Heat shock proteins (HSPs) are attractive therapeutic targets for neurodegenerative diseases, such as amyotrophic lateral sclerosis (ALS), characterized by aberrant formation of protein aggregates. Although motor neurons have a high threshold for activation of HSP genes, HSP90 inhibitors are effective inducers. This study evaluated NXD30001, a novel, small molecule HSP90 inhibitor based on the radicicol backbone, for its ability to induce neuronal HSPs and for efficacy in an experimental model of ALS based on mutations in superoxide-dismutase 1 (SOD1). In motor neurons of dissociated murine spinal cord cultures, NXD30001-induced expression of HSP70/HSPA1 (iHSP70) and its co-chaperone HSP40/DNAJ through activation of HSF1 and exhibited a protective profile against SOD1(G93A) similar to geldanamycin, but with less toxicity. Treatment prevented protein aggregation, mitochondrial fragmentation, and motor neuron death, important features of mutant SOD1 toxicity, but did not effectively prevent aberrant intracellular Ca(2+) accumulation. NXD30001 distributed to brain and spinal cord of wild-type and SOD1(G93A) transgenic mice following intraperitoneal injection; however, unlike in culture, in vivo levels of SOD1 were not reduced. NXD30001-induced expression of iHSP70 in skeletal and cardiac muscle and, to a lesser extent, in kidney, but not in liver, spinal cord, or brain, with either single or repeated administration. NXD30001 is a very useful experimental tool in culture, but these data point to the complex nature of HSP gene regulation in vivo and the necessity for early evaluation of the efficacy of novel HSP inducers in target tissues in vivo.
authors.affiliation: Montreal Neurological Institute and Department of Neurology/Neurosurgery, McGill University, 3801 University St, Montreal, QC, Canada, H3A 2B4.
authors.forename: Jieun R C
authors.initials: JR
authors.lastname: Cha
authors.forename: Kyle J H
authors.initials: KJ
authors.lastname: St Louis
authors.forename: Miranda L
authors.initials: ML
authors.lastname: Tradewell
authors.forename: Benoit J
authors.initials: BJ
authors.lastname: Gentil
authors.forename: Sandra
authors.initials: S
authors.lastname: Minotti
authors.forename: Zahara M
authors.initials: ZM
authors.lastname: Jaffer
authors.forename: Ruihong
authors.initials: R
authors.lastname: Chen
authors.forename: Allan E
authors.initials: AE
authors.lastname: Rubenstein
authors.forename: Heather D
authors.initials: HD
authors.lastname: Durham
mesh_terms: D000818:Animals; D002118:Calcium / Q000378:metabolism; D002470:Cell Survival / Q000187:drug effects; D002478:Cells, Cultured; D005727:Ganglia, Spinal / Q000187:drug effects / Q000378:metabolism; D049452:Green Fluorescent Proteins / Q000378:metabolism; D018841:HSP90 Heat-Shock Proteins / Q000037:antagonists & inhibitors* / Q000378:metabolism; D006360:Heat-Shock Proteins / Q000378:metabolism*; D006706:Homeostasis / Q000187:drug effects; D002479:Inclusion Bodies / Q000378:metabolism; D007783:Lactones / Q000008:administration & dosage / Q000493:pharmacokinetics / Q000494:pharmacology*; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D063154:Mitochondrial Dynamics / Q000187:drug effects; D009046:Motor Neurons / Q000187:drug effects / Q000378:metabolism; D009417:Nerve Tissue / Q000187:drug effects / Q000378:metabolism*; D010091:Oximes / Q000008:administration & dosage / Q000493:pharmacokinetics / Q000494:pharmacology*; D010766:Phosphorylation / Q000187:drug effects; D054852:Small Molecule Libraries / Q000008:administration & dosage / Q000493:pharmacokinetics / Q000494:pharmacology*; D013116:Spinal Cord / Q000187:drug effects / Q000378:metabolism; D013482:Superoxide Dismutase / Q000378:metabolism; D000072105:Superoxide Dismutase-1; D046509:Tissue Culture Techniques
chemical_list: D018841:HSP90 Heat-Shock Proteins; D006360:Heat-Shock Proteins; D007783:Lactones; D010091:Oximes; D054852:Small Molecule Libraries; C485184:enhanced green fluorescent protein; C555907:pochoxime A; D049452:Green Fluorescent Proteins; C000606291:Sod1 protein, mouse; D013482:Superoxide Dismutase; D000072105:Superoxide Dismutase-1; D002118:Calcium